Natural killer cell cytotoxicity (NKCC) against tumor may be important in preventing in vivo solid tumor dissemination. Multiple animal models demonstrate increased rates of tumor dissemination after surgical stress; previously we have observed that surgical stress impairs murine NKCC. Because of the importance of surgery in the control of solid tumor it may be valuable to examine the mechanism underlying surgical stress impairment of NKCC. Result of this research demonstrate that post surgical suppression of NKCC began as early as 2 hr after murine hind limb amputation, reached nadir at 4 days, and did not recover to control level until postoperative day 23. Anesthetic treatment alone did not cause comparable NKCC suppression. The suppression of NKCC accompanied changes in both splenic size and morphology. The immune suppression was observed in multiple compartments, including peripheral blood, bone marrow, and spleen. Mixing experiments demonstrated that surgical stress per se generated a suppressor cell population affecting NKCC; calibrated bleeding did not generate comparable suppression of NKCC. The observed suppression apparently required cell-to-cell contact since supernatants from 4 and 18 hr cultures of suppressor cells did not cause suppression. The observed suppression was prevented by perioperative treatment with the interferon inducing pyrimdinone analog 2-amino-5-bromo-6-phenyl-4-pyrimidinol (ABPP). These preclinical observations point to the future of NK specific perioperative immunotherapy that may help prevent possible tumor dissemination from occurring at the time of surgery.